APPLICANT'S ABSTRACT: Morbidity and mortality increase significantly when depression occurs concurrently with alcoholism, particularly in terms of suicide. New findings, in combination with common clinical practice, indicate tricyclic antidepressants (TCA's) have efficacy in treating alcoholic depressives. However, some alcoholics have lower TCA plasma levels than nonalcoholics, given the same oral dose, suggesting altered metabolism of TCA's in alcoholics. Alcohol is known to stimulate hepatic microsomal activities and may result in higher than standard metabolite levels in relation to the parent compound. The hydroxylated metabolites of TCA's (OH-TCA's) are biologically active and have been linked to therapeutic effect and toxicity. No study has looked at liver functioning in relation to TCA metabolism in recovering alcoholics and at consequent effects on response or toxicity, despite the common prescription of TCA's for depressed alcoholics. Therefore, it is of particular interest to pursue a fixed dose study of TCA treatment of recently abstinent alcoholics in whom liver function and TCA and OH-TCA plasma levels are assessed. The aminopyrine breath test (ABT) will be used to describe various degrees of impaired hepatic microsomal functioning that may related to different ways of metabolizing TCA's. Desipramine (DMI) has been chosen because it is a standard, efficacious TCA with generally mild side effects that has been identified as a preferred drug for treating depression in alcoholics and for studying the biochemistry of antidepressant response. Debrisoquine assays will be used to discriminate genetic from alcohol related abnormalities in DMI metabolism. Treatment will be of 6 months duration on the basis of preliminary findings that alcoholics' kinetic parameters for DMI return to near the mean for nonalcoholics after 6 months of abstinence. The ABT's of 40 non-depressed alcoholics, and the ABT's, DMI and OH-DMI plasma levels of 40 alcoholic depressives and 40 nonalcoholic depressives will be compared in a repeated measures design. The study is designed to test the hypotheses that (1) depressed alcoholics will differ from depressed nonalcoholics in DMI metabolism as reflected by plasma DMI and OH-DMI concentration, (2) DMI metabolism will normalize with abstinence and parallel changes will be found in hepatic microsomal functioning, and (3) OH-DMI will serve as a significant moderator of clinical response and side effects to DMI. This five year study will provide critically needed data re: treatment of depression in alcoholics, alcohol related changes in the metabolism of DMI, and normalization of these changes with continued sobriety.